Research leading to the completion of the invention was supported in part by Grant Nos. 3203522-12, RO1HL42817 and RO1DK49108 awarded by the National Institutes of Health (NIH). The United States Government has certain rights in and to the claimed invention.
1. Field of the Invention
The present invention relates to the treatment of inflammatory bowel diseases.
2. Description of the Prior Art
Inflammatory bowel disorders or diseases (IBD) encompass a spectrum of overlapping clinical diseases that appear to lack a common etiology. IBD, however, are characterized by chronic inflammation at various sites in the gastrointestinal (GI) tract. Illustrative IBD are regional enteritis (or Crohn""s disease), idiopathic ulcerative colitis, idiopathic proctocolitis and infectious colitis. Most hypotheses regarding the pathogenesis of IBD concern the implication of immunologic, infectious and dietary factors.
IBD are characterized histopathologically by ulceration, pseudomembranes, radiologically visible lesions, edema and the build-up of inflammatory cells; symptoms involve diarrhea, abdominal pain, weight loss and hypoproteinemia. Descriptions in the literature include Northfield, Drugs, Vol. 14, pages 198-206 (1977); Blaker et al, Eur. J. Pediatr., Vol. 139, pages 162-164 (1982); Singleton, The Gastroenterology Annual, pages 268-310 (1983); Saco et al, J. Amer. Acad. Dermatol., Vol. 4, pages 619-629 (1981); Prantera et al, Ital. J. Gastroenterol., Vol. 13, pages 24-27 (1981); Sales et al, Arch. Int. Med., Vol. 143, pages 294-299 (1983); and Ament, Inflammatory Bowel Diseases, Martinus Nijhoff Publ., Boston, Mass., pages 254-268 (1982). Less frequent, but also possible, are mucosal inflammation of other sections of the GI tract, such as duodenitis, jejunitis and proctitis.
The clinical manifestations of ulcerative colitis and Crohn""s disease share the common feature of inflammation. In ulcerative colitis, the earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkxc3xchn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration. The inflammatory involvement is diffuse and superficial, usually limited to the mucosa and submucosa.
The clinical picture includes cramping, lower abdominal pain or rectal bleeding, soon followed by frequent, loose discharges consisting mainly of blood, pus and mucus with scanty fecal particles. The rectum and ampulla are usually found to be spastic.
In Crohn""s disease (also known as regional enteritis or ulcerative ileitis), the most prominent feature of the disease is the granular, reddish-purple, edematous thickening of the bowel wall. In the early phase of the disease, the prominent irritability, spasm and edema give the appearance of a rigid contour to the diseased segment radiogenographically.
The histological picture consists of dilated and tortuous lymph vessels and granulomatous structures which are made up predominantly of epithelioid cells, lymphocytes and, occasionally, giant cells. With the development of inflammation, these granulomas often lose their circumscribed borders and merge with the surrounding tissue reaction. Obstruction is the predominant clinical feature. The stools, although loose, are rarely bloody.
Idiopathic ulcerative colitis (UC) is a recurrent acute and chronic ulcero-inflammatory disorder principally affecting the rectum and left colon, but sometimes the entire large bowel. See Kirsner et al, N. Engl. J. Med., Vol. 306, pages 775-837 (1982). UC encompasses a spectrum of diffuse, continuous, superficial inflammation of the colon which begins in the rectum and extends to a variable proximal level. See Cecil Textbook of Medicine, 19th Edition, page 699, Wyngaarden et al, ed., (1992). Matters relating to the etiology (i.e., definitive etiopathogenesis is not known), epidemiology, pathogenesis, pathology, symptoms, diagnosis (e.g., endoscopy and radiography) and complications (e.g., cancer, intestinal complications such as rectal bleeding and toxic megacolon, and extraintestinal complications such as anemia and leukocytosis) are set forth in relatively complete detail in the Cecil Textbook of Medicine, supra.
The manner in which UC is treated can vary and, typically, the medical treatment depends upon the severity of the symptoms exhibited by the patient. Corticosteroids (e.g., prednisone), antibiotics (e.g., tetracycline, sulfatrimethoprim, metronidazole and cephalexin) and immunosuppressants (e.g., 6-mercaptopurine and azathioprine) often are used for treating UC. Anti-inflammatory agents (e.g., sulfasalazine and mesalamine) are effective to some degree in some patients for the treatment of acute UC. Certain anti-inflammatory agents are available commercially as Asacol from Rolm Pharma GmbH, Dipentum from Kabi Pharmacia AB and Rowasa [5-aminosalicylic acid (5-ASA)] from Solvay Pharmaceuticals. In more severe cases or when the anti-inflammatory agents fail to relieve the symptoms of UC, surgical procedures are used. Typical surgical procedures include colectomy, proctocolectomy and ileostomy. See Cecil Textbook of Medicine, supra. Other treatment methods for gastrointestinal disorders have been proposed in U.S. Pat. Nos. 5,110,795 (Hahn), 5,112,856 (Gaginella et al), 5,216,002 (Gidda et al), 5,238,931 (Yoshikawa et al), 5,292,771 (Backstrxc3x6m et al), 5,312,818 (Rubin et al), 5,324,738 (Dinan et al), 5,331,013 (Ahlman et al), 5,340,801 (Ewing et al), 5,368,854 (Rennick), 5,391,555 (Marshall et al), 5,552,439 (Panetta), 5,569,680 (Wu), 5,599,795 (McCann et al), 5,604,231 (Smith et al), 5,691,343 (Sandborn) and 5,693,645 (Sharpe et al).
6-Mercaptopurine (6MP) and its prodrug azathioprine (AZA) have been used in the treatment of IBD for over twenty-five years. Multiple controlled trials and a recent meta-analysis support the efficacy of 6MP and AZA in Crohn""s disease. See Willoughby et al, Lancet, Vol. ii, page 944 (1971); and Rosenberg et al, Dig. Dis., Vol. 20, page 721 (1975). Several controlled trials support the use of AZA in ulcerative colitis, the most recent by Hawthorne et al in Brit. Med. J., Vol. 305, page 20 (1992). However, use of 6MP and AZA has been limited by concerns about their toxicities. Dose-related leukopenia is seen in 2-5% of patients treated long-term with 6MP or AZA for IBD. See, for example, Present et al, Am. Int. Med., Vol. 111, page 641 (1989); and Connell et al, Gut, Vol. 34, page 1081 (1993).
It is an object of the present invention to provide a novel and useful therapy for IBD.